Comparison of TGF-β, PDGF,and CTGF in hepatic fibrosis models using DMN,CCl4, and TAA

Three chemotoxins including dimethylnitrosamine (DMN), carbon tetrachloride (CCl₄), and thioacetamide (TAA) are commonly used in hepatofibrotic models. We aimed to draw characteristics of histopathology and pro-fibrogenic cytokines including TGF-β, PDGF and CTGF among three models. Rats were divided into six groups and intra-peritoneally injected with DMN (10?mg/kg, for three weeks, three consecutive days weekly), CCl₄ (1.6?g/kg, for 10 weeks, twice weekly), TAA (200?mg/kg, for 12 weeks, twice weekly) or their corresponded treatment for each control group. The liver weights were decreased in DMN model, but not other models. Ascites were occurred as 3-, 2-, and 7-rats in DMN, CCl₄, and TAA model, respectively. The lipid peroxidation was highest in CCl₄ model, serum levels of liver enzymes were increased as similar severity. The hepatofibrotic alterations were remarkable in DMN and TAA model, but not CCl₄ as evidenced by the Masson trichrome staining and hydroxyproline. The immunohistochemistry for α-SAM showed that the DMN model was most severely enhanced than other models. On the other hand, hepatic tissue levels of pro-fibrogenic cytokines including TGF-β, PDGF, and CTGF were generally increased in three models, but totally different among models or measurement resources. Especially, serum levels of three cytokines were remarkably increased by CCl₄ injection and CTGF levels in both hepatic tissue and serum were highest in CCl₄ group. Our results firstly demonstrated comparative study for features of morphological finding and pro-fibrogenic cytokines in serum and hepatic protein levels among three models. Above results would be a helpful reference for hepatofibrotic studies.     

Effect of sex hormones on lipid peroxidation in rat liver

The role of sex hormones in hepatic lipid peroxidation, and in hepatic aldehyde oxidase and xanthine oxidase activities were investigated using rat liver homogenates. It was observed that male rat had a significantly greater content of malondialdehyde in liver than female. Among the sex hormones tested, estradiol, one of female hormones, markedly inhibited the formation of lipid peroxides in liver tissues in vitro. Especially, the inhibitory effect of estradiol appeared more remarkably in Fe+2-induced lipid peroxidation. The hepatic xanthine oxidase activity was decreased about 15% by 10(-6) M estradiol, whereas, the aldehyde oxidase activity was almost completely disappeared at the same concentration of estradiol. It implies that sex differences in lipid peroxidation is attributed to the suppression of free radical generating system by estradiol.     

Tectorigenin, an isoflavone of Pueraria thunbergiana Benth., induces differentiation and apoptosis in human promyelocytic leukemia HL-60 cells

Cytotoxic effects of six isoflavonoids, tectorigenin, glycitein, tectoridin, glycitin, 6'-O-xylosyltectoridin, and 6'-O-xylosylglycitin isolated from the flower of Pueraria thunbergiana Benth. together with genistein, a known differentiation and apoptosis inducer, were examined. Among these isoflavonoids, tectorigenin and genistein exhibited cytotoxicity against various human cancer cells; glycitein showed only mild cytotoxicity. These results suggest that the isoflavone structure and 5-hydroxyl group are crucial for the cytotoxic properties and that glycosides are inactive. Moreover, tectorigenin induced differentiation of human promyelocytic leukemia HL-60 cells to granulocytes and monocytes/macrophages, and caused apoptotic changes of DNA in the cells, as did genistein. Tectorigenin also inhibited autophosphorylation of epidermal growth factor (EGF) receptor by EGF and decreased the expression of Bcl-2 protein, with less activity than genistein. From these results, tectorigenin may be a possible therapeutic agent for leukemia.     

Cocaine self-administration on a hold-down schedule of reinforcement in rats

Rationale and objective  Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. Materials and methods  Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. Results  Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. Conclusions  Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions. Drake Morgan and Yu Liu contributed equally to this publication.     

Nasal absorption studies of granisetron in rats using a validated high-performance liquid chromatographic method with mass spectrometric detection

Granisetron is a selective 5-HT3 receptor antagonist that is used therapeutically for the prevention of vomiting and nausea associated with emetogenic cancer chemotherapy. Although forms of the drug are commercially available for intravenous and oral dosage, there is a need for intranasal delivery formulations in specific patient populations in which the use of these dosage forms may be unfeasible and/or inconvenient. A rapid and specific high-performance liq uid chromatography method with mass spectrometric detection (LC-MS) was developed and validated for the analysis of granisetron in plasma after nasal administration in rats. Granisetron was separated in a reverse-phase C-18 column without interference from other components of plasma. This method involves a rapid assay for the determination of granisetron in a small volume of plasma with a run time of 12 min using ondansetron as an internal standard. Data were acquired in the electrospray ionization (ESI) mode with positive ion detection and application of single ion recording (SIR). Granisetron and ondansetron were detected at m/z values of 313.2 and 294.2, respectively. The method described was found to be suitable for the analysis of all samples collected during preclinical pharmacokinetic investigations of granisetron in rats after nasal administration. To date, the first pharmacokinetic study after intranasal administration of granisetron was performed and some pharmacokinetic parameters were presented in this paper. Granisetron was found to be well absorbed through nasal route and the bioavailability of this drug following nasal administration was comparable with that of intravenous administration.     

Preparation and evaluation of immediate release ibuprofen solid dispersions using polyethylene glycol 4000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), and evaluated for solubility, in-vitro drug release and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FT-IR spectra showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and Cmax, and a significant decrease in Tmax over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low temperature melting method using polyethylene glycol 4000 (PEG 4000) as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and absorption rate of ibuprofen.     

The effect of SonoPrep? on EMLA? cream application for pain relief prior to intravenous cannulation

The aim the study was to determine the effect of SonoPrep? on the delivery and analgesic effects of EMLA? cream prior to intravenous (iv) cannulation in a tertiary pediatric emergency department. Children aged between 5 and 10?years were enrolled. Patients were randomized to receive either sonophoresis with SonoPrep? or sham sonophoresis followed by application of EMLA? cream for 5?min prior to iv cannulation. The primary outcome measurement was the child's rating of pain immediately after iv placement, using a 10-cm visual analog scale (VAS). Parents or guardians and blinded researchers were additionally asked to rate their perception of the child's pain using the 10-cm VAS and the Wong-Baker Face scale. A total of 42 patients completed the study (21 in the study group, 21 in the control group). The baseline characteristics between the groups were similar. The VAS pain score was significantly lower in children treated with sonophoresis compared with the sham sonophoresis (median (percentiles 25th-75th), 20.0 (10.0-22.5) vs. 60.0 (31.0-87.5); p?相似文献